The present invention relates to the treatment of diseases involving a retinal ganglion neuron (RGC) degeneration, and in particular glaucoma.
The retina is the cell sheet which covers the back of the eye. It contains various types of neurons, the role of which is to capture light energy and to convert it into a nerve signal, and also glial cells.
Schematically, the retina comprises three main layers of neurons: photoreceptor neurons (cones and rods), bipolar neurons and ganglionic neurons; other neurons, amacrine neurons and horizontal neurons, play a regulatory role. The photoreceptor neurons react to light, and the signal that they generate is transmitted, by means of the bipolar neurons, to the ganglionic neurons, the axons of which constitute the nerve fibers of the optic nerve, ensuring that the information is sent to the brain.
Retinal neuron degeneration is involved in various retinopathies. Thus, photoreceptor neuron degeneration is involved in certain pathological conditions, such as retinitis pigmentosa or macular degeneration. In other pathological conditions, it is the ganglionic neurons which are affected. Damage to retinal ganglion neurons can be observed in various genetic or vascular optical neuropathies, but also more broadly in the context of neurodegenerative diseases (such as, for example, Alzheimer's disease, multiple sclerosis or Parkinson's disease).
One of the pathological conditions in which the predominant role of damage to the retinal ganglion neurons has been demonstrated is glaucoma. In this pathological condition, the degeneration of these neurons and of their axons results in a slow deterioration of the optic nerve, which can result in total blindness. The most common cause of glaucoma is intraocular hypertension. Although the mechanisms resulting in the destruction of ganglionic neurons are still poorly elucidated, its involvement in the occurrence of the pathological condition has been shown (Nickells, 2007, Can. J. Ophthalmol., 42, 278-87). In addition, in patients suffering from glaucoma, excessive concentrations of glutamate, a neurotransmitter normally present in the vitreous humor, have been observed (Dreyer et al., Arch Ophthalmol, 114, 299-305, 1996) (Morrison et al., Prog Retin Eye Res, 24, 217-240, 2005). At these concentrations, glutamate has a neurotoxic activity on ganglionic neurons in culture or in vivo (Hahn et al., Proc Natl Acad Sci USA, 85, 6556-6560, 1988; Li et al., Invest Ophthalmol V is Sci, 40, 1004-1008, 1999) (Shen and Slaughter, J Neurophysiol, 87, 1629-1634, 2002). TNF-alpha is also overexpressed in the retina and the optic nerve of patients suffering from glaucoma (Yuan and Neufeld, Glia, 32, 42-50, 2000; Tezel et al., Invest Ophthalmol V is Sci, 42, 1787-1794, 2001). The toxicity of this cytokine, associated with the presence of receptors on the ganglionic neurons, has been demonstrated in vitro (Fuchs et al., Invest Ophthalmol V is Sci, 46, 2983-2991, 2005) and in vivo (Fontaine et al., J Neurosci, 22, RC216, 2002).
The treatments currently available for glaucoma are based on molecules capable of reducing intraocular pressure (Woodward and Chen, Expert Opin Emerg Drugs, 12, 313-327, 2007).
Homeoproteins, or homeodomain proteins, are transcription factors which play a major role in the cell migration and differentiation phenomena involved in morphogenesis of the organism. They are characterized by the presence of a sequence of 60 amino acids, the homeoprotein, which is a DNA-binding domain, having a particular structure (helix/turn/helix). It has been shown that the isolated homeodomain of the Antennapedia protein of Drosophila can, firstly, cross the membrane of neurons in culture and, secondly, accumulate in the nucleus and promote neurite growth (application EP0485578 (Joliot et al., Proc Natl Acad Sci USA, 88, 1864-1868, 1991)). The penetration properties of the Antennapedia homeodomain are conferred by its third helix, and appear to be highly conserved between homeoproteins; its properties on neurite growth appear to be correlated with its DNA-binding properties, at the level of binding sites defined by the consensus sequence ANNNNCATTA (application EP0485578 (Joliot et al., Proc Natl Acad Sci USA, 88, 1864-1868, 1991)).
Otx2 (orthodenticle homolog 2) is a homeoprotein containing a bicoid-type homeodomain (Simeone et al., Embo J, 12, 2735-2747, 1993). It belongs to the Otx homeoprotein family, which plays a fundamental role in brain development during embryogenesis (Acampora et al., Prog Neurobiol, 64, 69-95, 2001; Simeone et al., Curr Opin Genet Dev, 12, 409-415, 2002). It has also been shown that Otx2 is involved in the formation of the retina, by promoting the differentiation of retinal stem cells into photoreceptor neurons. Application EP1591127 thus reports that transformation of retinal stem cells with a recombinant vector expressing Otx2 induces the differentiation of these cells into photoreceptor neurons, to the detriment of the other types of retinal neurons, and proposes the use of Otx2 for treating various retinal pathological conditions involving photoreceptor neuron degeneration.